One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Currently available medications reduce fracture risk but are unable to fully restore skeletal integrity. Thus, there remains an urgent need for osteoporosis treatments that rapidly and effectively restore bone strength. Unlike most chronic conditions, osteoporosis has historically been treated with only one drug at a time. Attempts to combine anabolic agents with the most commonly used antiresorptive agents (bisphosphonates) did not prove efficacious. In contrast, we recently reported that the combination of teriparatide and the receptor activator of nuclear factor-?B ligand (RANKL) inhibitor, denosumab, increases bone density and improves bone microarchitecture and estimated strength more than either drug alone and more than any available therapy. We have hypothesized that the efficacy of this combination is dependent on denosumab?s capacity to fully block teriparatide?s stimulation of bone resorption while allowing for teriparatide-induced stimulation of bone formation (modeling-based bone formation). In this proposal, we will directly assess the ability of teriparatide to stimulate modeling-based bone formation when bone resorption is blocked by denosumab. Furthermore, we will define the cellular and molecular mechanisms by which this combination achieves its efficacy. To accomplish these aims, we will perform a short-term clinical trial in which postmenopausal osteoporotic women are randomized to receive three-months of teriparatide, denosumab or both medications. Iliac crest bone biopsy specimens will then be sampled from all subjects after quadruple-labeling, an innovative technique that is able to assess the effects of short-term interventions on bone resorption and formation without requiring ?paired? biopsies in a single subject. With this technique, we are also able to evaluate treatment-induced changes in both static and dynamic indices of bone metabolism in each bone envelope separately (cancellous, endocortical, intra-cortical, and periosteal) and thus calculate the proportion of remodeling versus modeling- based bone formation in each skeletal compartment. Biopsy specimens will also be used for immunohistochemical evaluation of osteoblasts, osteoclasts, marrow adipocytes and signaling pathways that regulate osteogenesis. An additional 3.5-mm core will be obtained for RNA analyses of bone and the marrow microenvironment. Furthermore, cells will be isolated from marrow aspirates to evaluate for osteogenic potential (CFU-OB), lineage markers and signaling pathway activation. The successful completion of this study will allow us to better define the mechanisms that underlie the unparalleled efficacy of the specific combination of RANKL inhibition and PTH-receptor stimulation. This new understanding, in turn, will provide the framework for the design of studies with the potential to fundamentally advance osteoporosis treatment.